Drug delivery device with live button or user interface field

ABSTRACT

A drug delivery device includes a container for storing a drug, the container having a stopper for expelling the drug; an injection drive comprising an energy source for directly or indirectly acting on the stopper to expel the drug; a sensor for detecting contact between the drug delivery device and a body of a patient; and a user interface (UI) for activating or causing the activation of the injection drive. The device is operative for drawing attention to the UI, if the sensor detects contact between the drug delivery device and the body of the patient, to thereby indicate that the injection drive is ready to be activated, which activation is the next step in the drug administration process.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 15/522,387 filed Apr. 27, 2017, which is the UnitedStates National Stage of International Patent Application No.PCT/US2015/064869, filed Dec. 10, 2015, which claims the prioritybenefit of U.S. Provisional Application No. 62/094,516, filed Dec. 19,2014, the entire contents of each of the foregoing is expresslyincorporated herein by reference.

FIELD OF THE DISCLOSURE

The present disclosure relates to drug delivery devices. Moreparticularly, the present disclosure relates to drug delivery devices,which have an activation button or user interface that indicates whenthe device is ready to deliver or inject and suggests the next step inthe delivery or injection process.

BACKGROUND

Drug delivery devices, such as on-body injectors and hand-heldinjectors, are well known in the art. Such drug delivery devices may beconstructed as single use or reusable devices and may include componentswhich allow automatic operation of the device.

On-body and hand-held injectors may be commonly prescribed for patientsto self-administer medication, typically offering a preferred injectortype based on patient population and therapeutic needs. These injectiondevices can offer a compelling improvement to outcomes beyond a vial orprefilled syringe due to their ease of use and what may typically beconsidered a less intimidating injection process, among other factors.

It may be desirable to assist a patient in the self-administration of aprescribed medication. Unfortunately, on-body and/or hand-held injectorsmay appear complicated or intimidating to patients that are not familiarwith them. On-body injectors, for example, may have operational stepsincluding without limitation one or more of site preparation,unpackaging, adhesive liner removal, medication transfer, application tothe body, injection, removal, and disposal.

One of the opportunities to improve these injectors may be to clarifywhen the device is “ready to go” or “ready to inject” whilesimultaneously highlighting the next step in the process.

Accordingly, a drug delivery device is needed, which clarifies orindicates when the device is ready to go or inject while simultaneouslyhighlighting the next step in the drug administration process.

SUMMARY

Disclosed herein is a drug delivery device, a method of preparing a drugdelivery device, and a method of using a drug delivery device. Variousembodiments of the drug delivery device may comprise a container forstoring a drug, the container comprising a stopper for expelling thedrug; an injection drive comprising an energy source for acting directlyor indirectly on the stopper to expel the drug; a sensor for detectingcontact between the drug delivery device and a body of a patient; and auser interface (UI) for activating or causing the activation of theinjection drive; wherein attention is drawn to the UI by effecting anexternal state change of the UI, if the sensor detects contact betweenthe drug delivery device and the body of the patient, thereby indicatingthat the injection drive is ready to be activated.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is an elevational view of an on-body drug delivery deviceaccording to an embodiment of the disclosure.

FIG. 1B is an elevational view of a hand-held drug delivery deviceaccording to an embodiment of the disclosure.

FIG. 2A is perspective view showing the top of an on-body drug injectiondevice according to an embodiment of the disclosure.

FIG. 2B is perspective view showing the bottom of the on-body druginjection device of FIG. 2A.

FIG. 2C is an elevational view with certain elements shown incross-section of the on-body injection device of FIGS. 2A and 2B.

FIG. 2D is an enlarged elevational view of an embodiment of a deviceactivation mechanism illustrated in FIG. 2C.

FIGS. 3A and 3B are elevational views with certain elements shown incross-section, illustrating the operation of the on-body injectiondevice of FIGS. 2A-2D.

FIG. 4A is an elevational view with certain elements shown incross-section of an on-body injection device according to anotherembodiment of the disclosure.

FIG. 4B is an enlarged elevational view of a device activation mechanismillustrated in FIG. 4A.

FIG. 4C is cut away perspective view of the device of FIG. 4A whichillustrates one non-limiting method for connecting the switch assemblyto the needle insertion drive.

FIG. 4D is a plan view of a portion of the interior of the device ofFIG. 4A which illustrates one non-limiting method for connecting theswitch assembly to the stopper drive.

FIGS. 5A and 5B are elevational views with certain elements shown incross-section, illustrating the operation of the on-body injectiondevice of FIGS. 4A and 4B.

FIG. 5C is an enlarged elevational view of shown the operation of thedevice activation mechanism illustrated in FIGS. 4A and 4B.

FIG. 6 is perspective view showing the top of an on-body drug injectiondevice according to another embodiment of the disclosure.

FIGS. 7A-7C are perspective views showing the top of an on-body druginjection device according to a further embodiment of the disclosure.

FIG. 8 is a perspective view showing the top of an on-body druginjection device according to a further embodiment of the disclosure.

FIG. 9A is an elevational view with certain elements shown incross-section of a hand-held injection device according to an embodimentof the disclosure.

FIG. 9B is an elevational view with certain elements shown incross-section, illustrating the operation of the hand-held injectiondevice of FIG. 9A.

The same reference numerals are used in the drawings to identify thesame or similar elements and structures in the various embodiments.

GENERAL DESCRIPTION

Disclosed herein is a drug delivery device that includes a container, aninjection drive, a sensor and a device activation mechanism. Thecontainer is for storing a drug, and can have a stopper for expellingthe drug. The injection drive can include an energy source operablycoupled to the stopper for selectively moving the stopper through thecontainer to expel the drug. The sensor can have a first state when thedrug delivery device is out of contact with a body of a patient, and asecond state when the drug delivery device is in contact with the bodyof the patient. The device activation mechanism can be operably coupledto the sensor and the injection drive for selectively activating theinjection drive in response to user input. The device activationmechanism can undergo an external state change from a dormant state,when the sensor occupies the first state, to a ready state, upon thesensor occupying the second state, the ready state drawing attention tothe device activation member.

Also disclosed herein is a drug delivery device for drug delivery, whichin various embodiments comprises a container, an injection drive, asensor, and a user interface. The container may have a stopper forexpelling a drug stored in the container. The injection drive maycomprise an energy source for expelling the drug. The sensor detectscontact between the drug delivery device and a body of a patient and theuser interface activates or causes activation of the injection drive.Attention is drawn to the user interface, if the sensor detects contactbetween the drug delivery device and the body of the patient, therebyindicating that the injection drive is ready to be activated.

Further disclosed herein is a method for administering a drug, which invarious embodiments comprises providing a container for storing a drug,the container comprising a stopper for expelling the drug; providing aninjection drive comprising an energy source for directly or indirectlyacting on the stopper to expel the drug; providing a start member foractivating the injection drive; detecting contact between the drugdelivery device and a body of a patient with a sensor; drawing attentionto the start member, if the sensor detects contact between the drugdelivery device and the body of the patient, thereby indicating that theinjection drive is ready to be activated; and activating the injectiondrive with the start member after the attention has been drawn to thestart member.

Further disclosed herein is a method of preparing a drug delivery deviceto deliver a drug, which can include providing a drug delivery devicethat has a container, an injection drive, a sensor and a deviceactivation mechanism. The container is for storing a drug, and has astopper for expelling the drug. The injection drive includes an energysource operably coupled to the stopper for selectively moving thestopper through the container to expel the drug. The device activationmechanism is operably coupled to the sensor and the injection drive. Themethod further includes detecting contact between the drug deliverydevice and an injection site with the sensor, causing the sensor tochange from a first state to a second state. Then, when the sensoroccupies the second state, the method includes delivering contactinformation to the device activation mechanism with the sensor, thecontact information indicative of the relationship between the drugdelivery device and the injection site. Then, upon receiving the contactinformation, the method includes causing a physical appearance of atleast a portion of the device activation mechanism to change from adormant state to a ready state, thereby drawing attention to the deviceactivation mechanism to signal to a user that the drug delivery deviceis ready for use.

DETAILED DESCRIPTION

Referring now to FIGS. 1A and 1B, the drug delivery device may comprisea reusable or disposable injector or autoinjector which automaticallydelivers a subcutaneous injection of a fixed or user/patient-settabledose of a drug. As illustrated in FIG. 1A, various embodiments of thedrug delivery device may be configured as an on-body injection device orinjector 10 that attaches to the body of the patient and automaticallydelivers the drug over a controlled or predetermined period of time(e.g., from 30 seconds up to one or more hours). In various otherembodiments, as illustrated in FIG. 1B, the drug delivery device may beconfigured as a hand-held injection device or injector 20 that is placedmomentarily against the body of the patient and automatically deliversthe drug over a relatively short period of time (e.g., less than 10seconds). Such drug delivery devices are intended forself-administration (patient), but can of course be used by a caregiveror a formally trained healthcare provider (operator) to administer aninjection.

Referring again to FIGS. 1A and 1B, the injection device 10, 20 may beconfigured to draw the patient's or operator's attention to a userinterface (UI) such as a button-type actuator 12, 22, after a bodycontact sensor 14, 24 detects contact between the injection device 10,20 and the body of the patient, to signal or indicate that the injectiondevice 10, 20 is ready to be activated via the UI 12, 22, which is thenext step in the injection process. In some embodiments, readiness canbe signaled/indicated by effecting an external state change such as butnot limited to motion, sound, light, colors, and any combinationthereof. For example, in the embodiments shown in FIGS. 1A and 1B, theexternal state change comprises the raising or “popping out” of theactuator 12, 22. In other embodiments, the external state change cancomprise without limitation rotating the actuator, illuminating theactuator, changing the color of the actuator, revealing the actuator,generating a sound, generating a vibration, and any combination thereof.The placement of the injection device against the body of the patient invarious embodiments may unlock the UI and/or the device activationmechanism and cause the external state change which calls attention tothe UI. In various embodiments, the signal/indication and the unlockingUI and/or device activation mechanism can occur at approximately thesame time. In other embodiments, the pre-application state of the device(device not engaged with the body of the patient) may lock UI and/or thedevice activation mechanism such that the operation of signal/indicationfunction unlocks the UI and/or the device activation mechanism.

In various other embodiments, the removal of the device from the body ofthe patient without activation may lockout the UI and/or activationmechanism and return the UI to the original state (e.g., lower orconceal the actuator, turn off the illumination, sound, vibration, andany combination thereof). In such embodiments, the re-placement of thedevice against the body of the patient may unlock the UI and/or deviceactivation mechanism and cause the external state change, which callsattention to the UI.

FIGS. 2A-2D collectively illustrate an embodiment of an on-bodyinjection device 100 according to the present disclosure. The device 100comprises an outer casing 110, which can have a top wall 112, a base orbottom wall 114, and one or more side walls 116 that extend between thetop and bottom walls 112, 114. The top or side walls 112, 114 of thecasing 110 (top wall 112 as shown in FIG. 2A) may include a UI 164 whichallows the patient or operator to activate the device 100. As shown inFIG. 2B, the injection device 100 may further comprise an adhesive pad118 or any other suitable arrangement or mechanism for removablyattaching the device 100 to the body B of the patient. The adhesive pad118 may substantially cover the entire bottom wall 114 of the casing 110or one or more selected portions of the bottom wall 114. A removablesterile barrier film (not shown) may be provided for covering theadhesive pad 118 prior to use of the device 100. The bottom wall 114 ofthe casing 110 and the adhesive pad 118 can include a first pair ofcoaxially aligned openings 120 which allow an injection needle 138(FIGS. 2C and 3B) or any other suitable drug delivery member, element,or device, to extend out from the device casing 110 during the injectionprocess to penetrate the body B (e.g., skin) of the patient. Adepressible body sensing pin 192 or other depressible or deflectablemember of an electromechanical body contact sensor 190, may extendthrough a second pair of coaxially aligned openings 122 defined in thebottom wall 114 of the casing 110 and the adhesive pad 118. The bodysensing pin 192 or deflectable member may be depressible or deflectablein a linear, rotational, or compressive manner. The body contact sensor190 may include a sensor that changes from a first state to a secondstate upon contacting an injection site such as a patient's body and maybe capable of communicating sensor information to the device activationmechanism 160 through a central processing unit 194, a mechanicallinkage, or otherwise. Electromechanical sensors may include switchesand the like for monitoring the movement of the pin or other depressibleor deflectable member as it is depressed or deflected during the bodysensing process. Compressive depressible and deflectable members may beimplemented with a compressible pad. Such sensors may use capacitive orresistive methods to detect pad compression. In various otherembodiments, the body contact sensor 190 may comprise an electricalsensor, such as but not limited to a capacitive sensing device, animpedance sensor, or a proximity sensor, such as but not limited to aninfrared proximity or distance sensor, which do not use depressible ordeflectable pins or other members. In still further embodiments, thebody contact sensor 190 may comprise a purely mechanical sensor or anoptical sensor for sensing contact between the device 100 and the body Bof the patient and changing from a first state to a second state uponsaid contact.

As shown in FIG. 2C, the on-body injection device 100 may furthercomprise a medicament container 130 for storing a drug to beadministered to a patient, an injection drive comprising a stopper drive140 and/or a needle insertion drive 150, a device activation mechanism160 and switch lifting mechanism 180. The casing 110 in reusableembodiments of the device 100 may be configured to allow removal andinsertion of the medicant container 140. For example, in someembodiments of the device 100, the casing 110 may have a closure (notshown) that allows insertion and removal of the medicament container130. In other embodiments of the device 100, the casing 110 mayconfigured so that the bottom wall 114 can be removed from the rest ofthe casing 110 to allow insertion and removal of the medicamentcontainer 130.

In various embodiments, the medicament container 130 may be pre-filledwith the drug 132. A stopper 134 may be movably disposed within themedicament container 130 for expelling the drug 132 from the container130. A tube 136 may be provided for fluid coupling the medicamentcontainer 130 to a remotely located injection needle 138, therebyallowing the drug 132 to be expelled from the container 130 anddispensed by the injection needle 138

The stopper drive 140 acts on the stopper 134 to move it through themedicament container 130 to expel the drug 132 therefrom. In variousembodiments, the stopper drive 140 may comprise a plunger and an energysource for propelling the plunger. The energy source may comprise amechanical arrangement of one or more springs or anelectrical/mechanical arrangement comprising one or more motors and/orsolenoids and a drive train or transmission, or an arrangement thatgenerates or releases a pressurized gas or fluid. In other embodiments,the stopper drive may comprise an arrangement that generates or releasesa pressurized gas or fluid which acts directly on the stopper to movethe stopper through the medicament container 130.

The needle insertion drive 150 may be configured to move the injectionneedle 138 between first and second positions. In the first position,the injection needle 138 may be disposed entirely within the interior ofthe casing 110 and concealed from view as shown in FIG. 3A. In thesecond position, at least a portion of the injection needle 138 mayextend out through the openings 122 in the bottom wall 114 of the casing110 and adhesive pad 118, as shown in FIG. 3B.

The CPU 194 or like device may be housed in the casing 110 or locatedremotely from the device 100. The CPU 194, the device activationmechanism 160 and the body contact sensor 190 may operate together toactivate, deactivate, and/or control the stopper drive 140 and/or needleinsertion drive 150. In some embodiments, the CPU 194 may control thestopper drive 140 so that the device 100 administers the drug to thepatient at a controlled rate. The CPU 194 may also be configured toallow the patient or operator to set the drug administration rate of thedevice 100. In other embodiments, the CPU 194 can be configured tocontrol the activation sequence and/or deactivation sequence of thestopper drive 140 and the needle insertion drive 150.

The device activation mechanism 160 initiates, triggers, or activatesthe device 100 in response to a patient or operator input at the UI 164.As shown in FIGS. 2C and 2D, the UI 164 and the device activationmechanism 160 may be integrated into a single component comprising anelectromechanical switch assembly 162 where the UI 164 is implemented asa depressible actuator. In other embodiments, the UI and deviceactivation mechanism may be separate, operatively connected components.The device activation mechanism 160 communicates switching informationto the CPU 194, which in response, activates one or both of the needleinsertion drive 150 and stopper drive 140.

Referring still to FIG. 2C and FIG. 2D, the switch lifting mechanism 180(switch lift) may be mounted on the bottom wall 114 of the device casing110, for changing the external state of the device activation mechanism160. Specifically, the switch lift 180 is for raising the switchassembly 162 of the device activation mechanism 160 from a dormant state(i.e., a lowered position) as shown to a ready state (i.e., a raisedposition) within the casing 100 (FIG. 3A) when the device 100 isproperly engaged or in contact with the body B of the patient to bringattention to the UI/actuator 164. The switch assembly 162 may include alatch 170 which unlocks the UI/actuator 164 and therefore, the deviceactivation mechanism 160. The switch assembly 162 may ride in a guidechannel 176 formed within the device casing 100, as it is raised andlowered by the switch lift 180. The CPU 194 controls the switch lift 180based on signals the CPU 194 receives from the body contact sensor 190.Specifically, if the body contact sensor 190 sends a signal indicatingthat the device 100 is properly engaged with the body B of the patient,and therefore occupying the second state, the CPU 194 can send a signalto the switch lift 180 which causes it to raise the switch assembly 162from the formant state to the ready state. This changes in outwardappearance of the device activation mechanism 160 by causing the switchassembly 262 to prominently protrude out of the drug delivery device100. If after raising the switch assembly 162 and prior to the patientactivating the device 100 via the UI/actuator 164, the CPU 194 receivesanother signal from the body contact sensor 190 that the deviceactivation mechanism 160 has partially or completely disengaged from thebody B of the patient, therefore occupying the first state, the CPU 194can cause the switch lift 180 to lower the switch assembly 162, therebyre-locking the UI/actuator and the device activation mechanism 160.

In addition to the depressible UI/actuator 164, the electromechanicalswitch assembly 162 may further comprise a switch housing 166 and anactivation switch 168 disposed in the switch housing 166. TheUI/actuator 164 may telescopically move relative to the switch housing166 between first (undepressed) and second (depressed) positions. TheUI/actuator 164 may be flush with or recessed from the casing 110 (e.g.,top wall 112) when the device 100 is in a not-ready-to-inject state,which is also referred to herein as the dormant state, i.e., where theswitch assembly 162 is in the lowered position and the UI/actuator 164is in the undepressed position. The latch 170 can be rotatively coupledto the UI/actuator 164 for locking the UI/actuator 164 in the firstposition if the switch assembly 162 is in a lower position (i.e.,dormant state or not-ready-to-inject state) within the device casing110.

As best illustrated in FIG. 2D, the switch housing 166 may have acup-like structure formed by a cylindrical side wall 166 sw, a base wall166 bw closing a bottom end of the side wall 166 sw and an outwardlyextending flange 166 f disposed at the open top end of the side wall 166sw. The UI/actuator 164 may have a plug-like structure formed by abutton member 164 b and a resilient side wall 164 sw depending fromperimeter of the button member 164 b. The latch 170 may comprise aplanar, triangular structure comprising a base edge surface 170 b, aconvex first side edge surface 170 si, and a flat second side edgesurface 17052, and a pivot pin 170 p disposed or formed at theintersection of the first and second side edge surfaces 170 si, 170 s 2.The pivot pin 170 o rotatively mounts the latch 170 within a slot 164 s1 formed in the side wall 164 sw of UI/actuator 164, adjacent to or at atop end thereof. When the injection device 100 is in the dormant statewhere the switch assembly 162 is in the lower position and theUI/actuator 164 is in the first, undepressed position, the latch 170 isfree to rotate down so that the base edge 170 b surface faces the flange166 f of the switch housing 166, thereby locking the UI/actuator 164 soit cannot be depressed. A detent arrangement may be provided for settingthe first and second positions of UI/actuator 164 in the switch housing166. The detent arrangement may comprise a protruding catch element 172formed on the outer surface of the UI/actuator side wall 164 sw or theinner surface of the switch housing side wall 166 sw and a pair ofnotches 174 formed on the other one of the UI/actuator side wall 164 swand switch housing side wall 166 sw. The activation switch 168 may bemounted on the base wall 166 bw of the switch housing 166 below theUI/actuator 164. The activation switch 168 may comprise anelectromechanical switch or any other suitable switch capable ofcommunicating switching information to the CPU such as but not limitedto a capacitive, inductive or touch-sensitive switch.

As described earlier, the switch assembly 162 can be raised or loweredbetween the dormant and ready states in the guide channel 176. One ormore locking pins 178 (FIG. 3B) may be provided for locking the switchassembly 162 in the raised position. The one or more locking pins 178may extend through openings 179 in the guide channel 176 w and the sidewall of the switch housing 166 which align with one another when theswitch assembly 162 is in the raised position. In various embodimentsthe locking pins 178 may be implemented with pin solenoids 178 ps, asillustrated in FIG. 2D. In various other embodiments, the pins 178 maybe biased toward the switch assembly 162 by a biasing member, such asbut not limited to a spring (not shown).

The switch lift 180 may comprise without limitation a linear actuator oran electrical solenoid 181, mounted on the bottom wall 114 of the casing110 below the switch housing 166 and a biasing member 182. In someembodiments, the actuator or solenoid 181 may be configured to raise theswitch assembly 162 from the lowered position (FIGS. 2C and 2D) into theraised position (FIGS. 3B and 3C), and the biasing member 182 may beconfigured to bias the switch assembly 162 toward the lowered positionso that when the actuator or solenoid 181 is deactivated, the biasingmember 182 maintains the switch assembly 162 in the lowered position orreturns the switch assembly 162 from the raised position to the loweredposition. In such embodiments, the biasing member 182 may comprise butis not limited to an extension spring.

In other embodiments, the actuator or solenoid 181 may be configured tomaintain the switch assembly 162 in the lowered position or to lower theswitch assembly 162 to the lowered position from the raised position,and the biasing member 182 may be configured to raise the switchassembly 162 from the lowered position to the raised position. In suchembodiments, the biasing member 182 may comprise but is not limited to acompression spring.

FIGS. 3A and 3B illustrate the external state change features of theinjection device 100 of FIGS. 2A-2D. FIG. 3A, illustrates the injectiondevice 100 after it has been properly placed in contact with the body Bof a patient during the device mounting process. As the device 100 ismounted to the body B, the body contact information sensed by thesensing pin 192 of the body contact sensor 190 retracting from the firststate to the second state is communicated to the CPU 194. In response tothe body contact information, the CPU 194 activates the switch lift 180to raise the switch assembly 162, which causes the UI/actuator 164 torise or “pop out” of the device casing 110 and into the ready state,thereby drawing the patient's or operator's attention to the UI/actuator164. The UI/actuator 164 may now be disposed above the exterior surface(e.g., top wall 112) of the casing 110, as shown in FIG. 3A, or in someother position relative to the casing 110. Once in the switch assembly162 is in the ready state, it occupies the raised position and thelocking pins 178 enter the openings 179 in the wall 176 w of the guidechannel 176 and side wall 166 sw the switch housing 166 to lock theswitch assembly 162 in the raised position. As the switch assembly 162rises, the latch 170 engages the interior surface of the casing 110(e.g., top wall 112) and rotates and unlocks the UI/actuator 164, whichplaces the injection device 100 in the ready state, which can also bereferred to as the ready-to-inject state. The motion or change in stateof the UI/actuator 164, thus, signals to the patient or operator thatthe next step in the injection administering process is to depressUI/actuator 164.

FIG. 3B illustrates the injection device 100 after the patient oroperator has depressed the UI/actuator 164 and moved it from the firstundepressed position to the second depressed position as set by thedetent arrangement 172, 174. As the UI/actuator 164 enters the seconddepressed position it engages or otherwise activates the activationswitch 168. Once activated, the activation switch 168 communicates theswitching information to the CPU 194. In response, the switchinginformation, the CPU 194 activates the needle insertion drive 150 todrive the injection needle 138 in the body B of the patient and thestopper drive 140, which expels the drug 132 stored in the medicamentcontainer 130 through the injection needle 138 and into the patient'sbody B.

FIGS. 4A-4D collectively illustrate another embodiment of the on-bodydrug injection device 200. The device 200 is similar to the device 100shown in FIGS. 2A-2D and 3A-3B, except that the device activationmechanism 260 comprises a UI/actuator 264 integrated into a mechanicalswitch assembly 262 and a mechanical body contact sensor 290 that alsofunctions as a switch lift. As can be seen, the user mechanical switchassembly 262 may be directly coupled to a sensing pin 292 of themechanical body contact sensor 290. The mechanical body contact sensorcan be mounted, for example, on the bottom wall 114 of the device casing110. In other embodiments, the UI/mechanical switch assembly may becoupled to the sensing pin of the mechanical body contact sensor by alinkage or other mechanism (not shown).

The sensing pin 292 of the body contact sensor 290 may include a firstend 2921 which acts on the switch assembly 262 and a second end 2922which contacts the body B of the patient when the device 200 is mountedthereon. In addition to the sensing pin 292, the mechanical body contactsensor 290 can comprise a housing 291 which contains the sensing pin 292and a biasing element 293. The sensing pin 292 may extend longitudinallythrough the housing 291 so that each end 2921, 2922 of the pin emergesfrom an end the housing 291. The biasing element 293 may comprise aconical compression spring or like biasing element having a first end293 ₁ seated on a first annular support member 291 ₁ affixed to theinterior surface of the housing 291 adjacent to and spaced from the top291 t of the housing 291 and a second end seated 293 ₂ on a secondannular support member 2912 affixed to the outer surface of the sensingpin 292 adjacent to and spaced from the second end 292 ₂ of the pin 292.The biasing element 293 biases the sensing pin 292 in the direction ofthe body B so that it extends out through the openings 122 in the bottomwall 114 of the device casing and pad 118 when the pin 292 is notdepressed.

Referring still to FIGS. 4A-4D, the mechanical switch assembly 262 maycomprise a switch base 266, the depressible UI/actuator 264, and atrigger wire or cable 294 extending through the switch assembly 262. Theswitch base 266 may comprise a cylindrical side wall 266 sw and a bottomwall 266 bw closing a bottom end of the side wall 266 sw. The centralportion of the bottom wall 266 bw may be configured to form a receptacle266 r that receives the first end 2921 of the sensing pin 292. Thecentral portion of bottom wall forming the receptacle 266 r and the sidewall 266 sw of the switch base 266 define an annular crimping channel266 c. The UI/actuator 264 may have a cap-like structure comprising abutton member 264 b and a side wall 264 sw depending from perimeter ofthe button member 264 b. The UI/actuator 264 may be telescopicallymovable relative to the switch base 266 between first and secondpositions. The button member 264 b may include one or more crimp arms264 a that extend from the interior surface thereof and face thecrimping channel 266 c of the switch base 266. A stop flange 264 f mayextend outwardly from the bottom edge of the UI/actuator side wall 264sw. The trigger wire 294 may have a first end 2941 anchored to aninterior surface, wall, or member 110 a of the casing 110 and a secondend 2942 operatively connected to trigger the needle insertion drive 150and/or stopper drive 140 when the trigger wire 294 is crimped betweenthe UI/actuator 264 and the switch base 266, as will be explainedfurther on in greater detail.

FIG. 4C illustrates one non-limiting method for operatively connectingthe switch assembly 262 (FIGS. 4A and 4B) to the needle insertion drive150. As illustrated, the needle insertion drive 150 may comprise adiscontinuous or segmented needle holder guide wall 152, a needle holder154 that holds the injection needle 138, and a compression spring 156(FIG. 4A) disposed between the needle holder 154 and the top wall 112 ofthe casing 110 which biases the needle holder 154 towards the needleextended position when the needle holder 154 is raised in the needleconcealed position. The needle holder guide wall 152 extends up from thebottom wall 114 of the casing 110 and guides the needle holder 154 as itis propelled down during needle insertion. A lock-out pin 158 or othersuitable projection which may extend laterally from the needle holder154, rests on the top edge 152 t of the needle holder guide wall 152 tohold the needle holder 154 in the needle concealed position, prior toactivation of the device 200. The second end 2942 or other portion ofthe trigger wire 294 of the switch assembly 262 may wrap around theneedle holder 154. When the UI/actuator 264 (FIGS. 4A and 4B) of theswitch assembly 262 is depressed, the trigger wire 294 is pulled in thedirection of arrow A1, which in turn rotates the needle holder 154 a fewdegrees and causes the pin 158 to slide off the top edge 152 t of theneedle holder guide wall 152, thereby activating the needle insertiondrive 150. Once activated, the compressed compression spring 156 of theneedle insertion drive 150 propels the needle holder 154 down throughthe guide wall 152 so that the injection needle 138 extends out from thebottom wall 114 of the casing 110 and penetrates the body tissue of thepatient.

FIG. 4D illustrates one non-limiting method for operatively connectingthe switch assembly 262 (FIGS. 4A and 4B) to the stopper drive 140. Asillustrated, the stopper drive 140 may comprise a hollow plunger 142, acompression spring 144 disposed within the plunger 142 between a workingend wall 142 ew of the plunger 142 and a backstop wall 148 providedwithin the casing 110, a spring release rod 146 extending through thespring 144 having a first end 1461 affixed to the working end wall 142ew of the plunger 142 and a second end 1462 extending through an opening148 o in the backstop wall 148, and a delivery lock-out pin 149 whichextends through an opening 146 o in the second end 1462 of the springrelease rod 146. A secondary wire or cable 294 s extending from theneedle holder 154 of the needle insertion drive 150, may be connected tothe lock-out pin 149. Therefore, when the switch assembly 262 activatesof the needle insertion drive 150 as described above, the needle holder154 pulls the secondary wire 294 s in the direction of arrow A2, therebywithdrawing the lock-out pin 149 from the opening 146 o in the secondend 1462 of the spring release rod 146 and thereby releasing it andactivating the stopper drive 140. Once activated, the compressedcompression spring 144 of the stopper drive 140 propels the plunger 142against the stopper 134 and drives it through the medicament container130 to expel the drug 132 stored therein though the injection needle 138and into the patient's body B.

The UI/actuator 264 may be flush with or recessed from the casing 110(e.g., top wall 112) when the device 200 is in the not-ready-to-injectstate, which is also referred to as the dormant state i.e., where theswitch assembly 262 is in the lowered position and the UI/actuator 264is in the first undepressed position (e.g., the device 200 not properlycontacting the body B of the patient). If the patient or operatorattempts to depress the UI/actuator 264 to move it from the firstposition to the second position in the dormant state, the stop flange264 f will engage the top 291 t of the body contact sensor housing 291,thereby locking the UI/actuator 264 and preventing the activation of thedevice 200. Raising switch assembly 262 to the ready state creates aspace of gap G between the stop flange 264 f and the top 291 t of thebody contact sensor housing 291 (FIG. 5A), which effectively unlocks theUI/actuator 264 and allows it to be depressed to the second depressedposition.

The sensing pin 292 of the body contact sensor 290 raises the switchassembly 262 to the ready state within the casing 110 of the device 200if the device 200 is properly contacting the body B of the patient suchthat the body contact sensor 290 occupies the second state to bring theUI/actuator 264 to the attention of the patient or operator and tounlock the UI/actuator 264 and the device activation mechanism 260.

FIGS. 5A-5C illustrate the external state change features of theinjection device of FIGS. 4A-4D. FIG. 5A, illustrates the injectiondevice 200 after it has been properly placed in contact with the body Bof a patient during the device mounting process. As the device 200 ismounted to the body B, the sensing pin 292 of the body contact sensor290 retracts into the device casing 110 thereby compressing the biasingelement 293 and raising the switch assembly 262 from a lowered positioncorresponding to the dormant state to and a raised positioncorresponding to the ready state. The raising of the switch assembly 262causes the UI/actuator 264 to rise or “pop out” of the device casing110, thereby drawing the patient's or operator's attention to theUI/actuator 264. The raising of switch assembly 262 also unlocks theUI/actuator 264 (creates the gap G between the stop flange 264 f and thetop 291 t of the body contact sensor housing 291), which places theinjection device 200 in the ready-to-inject state, which is alsoreferred to as the ready state. The UI/actuator 264 may now be disposedabove the exterior surface of the casing 100 (e.g., top wall 112) asshown in FIG. 5A, or in some other position relative to the casing 110.As the switch assembly 262 rises, the switch base 266 pulls the secondend 2942 of the trigger wire 294 which is operatively connected to theneedle insertion drive 150 and/or stopper drive 140 toward the switchassembly 262 a first distance, but this distance is not effective foractivating the needle insertion drive 150 and/or stopper drive 140.

FIG. 5B illustrates the injection device 200 after the patient oroperator has depressed the UI/actuator 264 and moved it from the firstundepressed position to the second depressed position, in response tothe motion or change in state of the UI/actuator 264 which signals thepatient or operator that the next step in the injection administeringprocess is to depress UI/actuator 264. As the UI/actuator 264 isdepressed into the second position the crimp arms 264 a engage thetrigger wire 294 and press it into the crimp channel 266 c of the switchbase 266, as best shown in FIG. 5C.

Referring again to FIG. 5B, the crimping of the trigger wire 294 pullsthe operatively connected second end 2942 of the trigger wire 294 anadditional second distance toward the switch assembly 262, which issubstantially greater than the first distance. The pulling of the secondend 2942 of the trigger wire 294 the first and second distancesactivates the needle insertion drive 150 to drive the injection needle138 into the body B of the patient and activates the stopper drive 140,which expels the drug 132 stored in the medicament container 130 thoughthe injection needle 138 and into the patient's body B.

To aid in attracting the attention of the patient or operator, theinjection devices described above include state changes represented byphysical movements that change the outward appearance of the deviceactivation mechanism 260 by changing the physical location, orientation,and/or configuration of the switch assembly 262 relative to theremainder of the drug delivery device 200. The external state changes,however, may also be configured to illuminate the UI/actuator as itrises, the side wall of the UI/actuator may illuminate or be brightlycolored, a sound may be made by an audio speaker contained in theinjection device as the UI/actuator rises, a vibration mechanism may bevibrated, and any combination thereof. As such, the outward appearanceof the device activation mechanism 260 may be changed by way of lightingand/or exposing a distinctly colored portion that was previouslyconcealed when the device activation mechanism 260 occupied the dormantstate. Moreover, while emitting a sound and vibrating the deviceactivation mechanism 260 do not change the outward appearance of thedevice activation mechanism 260, these do effect an external statechange that is recognizable to a user. As such, sounds and vibrationsand the like are included within the meaning of external state changeused herein.

FIG. 6 illustrates an embodiment of an on-body injection device 300which may comprise a button-type UI/actuator 364 which is configured torotate or spin as they rise or “pop-up” from the dormant state to theready state, to further attract the attention of the patient oroperator. In such embodiments, the UI/actuator 364 may include an iconthat spins as the UI/actuator 364 spins, the UI/actuator 364 mayilluminate as it spins, the side wall 364 sw of the UI/actuator 364 mayilluminate or be brightly colored, a sound may be made by an audiospeaker (not shown) contained in the injection device 300 as theUI/actuator 364 spins, vibrations may be imparted on the device 300 witha vibration generator, and any combination thereof. Thus, it should beappreciated that the external state change can include physicalmovement, but can also include non-physical changes such asillumination, audio, tactile (e.g., vibrations), etc. Indeed, in someversions, the state change may not include any physical movement at all,but rather merely simply some audio and/or visual indication.

The UI/actuator may also comprise a display that turns on if the bodycontact sensor of the injection device senses proper contact with thebody of the patient, and thereby changes from the dormant state to theready state, to attract the attention of the patient or operator andsignal the next step of the injection process. Such a display wouldeffect change to the outward appearance of the device activationmechanism. FIGS. 7A-7C illustrate an on-body injection device 400comprising a UI/actuator 464 implemented as a display, such as acapacitive or resistive touchscreen display. The UI/actuator 464 may beconcealed behind a closure 464 c 1 that slidably opens to reveal theUI/actuator display 464, as the body contact sensor (not visible) of theinjection device 400 senses proper contact with the body of the patient.In such embodiments, further attention may brought to the UI/actuatordisplay 464 by causing it to display flashing or brightly colored imagesas it turns on or is revealed by the closure 464 c 1. In addition, asound may be combined with the turning on or revealing of theUI/actuator 464 in such embodiments, which sound can be made by an audiospeaker (not shown) contained in the injection device 400. Thus, inFIGS. 7A-7C, the external state change can include a dormant statewherein a display is turned off and/or concealed behind the closure 464c 1 and the ready state can include the closure 464 c 1 being removedand/or the display is illuminated or otherwise activated and/or an audioand/or visual signal is emitted.

FIG. 8 illustrates an on-body injection device 500 comprising abutton-type UI/actuator 564 concealed by a sliding closure 564 c 1,which opens as the body contact sensor (not visible) of the injectiondevice 500 senses proper contact with the body of the patient, to allowthe UI/actuator 564 to rise or “pop out” from the casing 510.

FIG. 9A illustrates an embodiment of a hand-held injection device 600according to the present disclosure. The injection device 600 canincludes an elongated outer casing 610, a syringe 630 or othermedicament container, a stopper drive 640, a device activation mechanism660, and a body contact sensor 690, and a lift linkage 680.

The syringe 630 can include a barrel 631 for storing a drug 632, aninjection needle 638 or any other fluid dispensing element suitable forinjecting the drug into the body, and a stopper 634 disposed in thebarrel 631 of the syringe 630. In some embodiments, the syringe 630 maybe prefilled with the drug 632.

The stopper drive 640 can include a plunger 642 for driving the stopper634 through the barrel 631 of the syringe 630 to inject the drug 632,and a spring 644 or other energy source for propelling the plunger 642to perform the drug injection or both needle insertion (e.g.,embodiments where the syringe 630 is adapted to axially move relative tothe casing) and drug injection. The plunger 642 may extend through thespring 644 so that the one end of the spring 644 engages a head member646 of the plunger 642 and the other end of the spring 644 engages thedevice activation mechanism 660. Prior to operation of the injectiondevice 600, the spring 644 may be compressed between the head member 646of the plunger 642 and the drive activation mechanism 660, therebygenerating a spring biasing force against the head member 646 of theplunger 642 and the drive activation mechanism 660. When the injectiondevice 600 is operated by activating the device activation mechanism 660the spring 644 expands distally thereby propelling the plunger 642.

The device activation mechanism 660 may comprise a mechanical triggerassembly 662 having an actuator 664 that forms the UI, and a plungerrelease member 668. The UI/actuator 664 may have a button-like structurewhich is flush with or recessed from the device casing 610 when thedevice activation mechanism 660 is in the not-ready-to-use state, whichis also referred to as a dormant state, i.e., when the trigger assembly662 is in a first position and the UI/actuator 664 is in an undepressedposition. The UI/actuator 664 may be connected to or otherwise disposedat a first end 6681 of a plunger release member 668. A second end 6682of the plunger release member 668 may include a sleeve element 670 thatslidably receives the lift linkage 680. The plunger release member 668can include a latch (not visible), which holds the plunger 642 in anarmed position prior to operation of the injection device 600 and whichreleases the plunger 642 when the UP actuator 664 is depressed towardthe device casing 610 to activate the injection device 600 to administeran injection. Once released, the spring 644 propels the plunger 642through the barrel 631 of the syringe 630 thereby driving the stopper634 and expelling the drug 632 from the barrel 631 and out through theinjection needle 638.

The body contact sensor 690 may be a mechanical sensor comprising atubular sensing member 692 which is also operative as a needle guard.The sensing member 692 can be movably disposed at the distal end 610 deof the casing 610, and may be biased in an extended position(corresponding to a first state) by a biasing element (not shown), suchas but not limited to a spring, which allows it to retract toward thecasing 610 into a second state when the injection device 600 is pressedagainst the body of the patient. When the sensing member 692 is in theextended position (first state) it may surround or cover the injectionneedle 638.

The lift linkage 680 connects the sensing member 692 of the body sensor690 to the trigger assembly 662 of the device activation mechanism 660.The lift linkage 680 may comprise an elongated rod section 682, a bentrod section 684, and a slide rod section 686. The elongated rod section682 may have one end connected to the sensing member 692 and the otherend connected to or merging with an end of the bent rod section 684. Theother end of the bent rod section 684 may be connected to merges with anend of the sliding rod section 686. The bent rod section 684 spaces thesliding rod section 686 away from a cam element 688 disposed on theinterior surface of the casing 610. The sliding rod section 686 isslidably received within the sleeve element 670 at the second end 6682of the plunger release member 668.

Referring to FIG. 9B, as the injection device 600 is pressed against thebody B of the patient during the process of administering an injection,the sensing member 692 of the body contact sensor 690 retractsproximally into the casing 610 to occupy the second state, therebymoving the lift linkage 680 proximally (arrow P). As the lift linkage680 moves proximally, the sliding rod section 686 can slide freelythrough the sleeve element 670 of the plunger release member 668, whileremaining connected therewith. The length of the bent rod section 684 isselected so that when a body contact threshold is reached, a proximalend 682 p of the elongated rod section engages the cam 688 disposed onthe interior surface of the device casing 610 and deflects the elongatedrod section 682 toward the plunger release member 668. The deflection ofthe elongated rod section 682 causes the sliding rod section 686 to movethe trigger assembly 662 laterally within the device casing 610 therebycausing the UI/actuator 664 to rise or “pop out” from its dormant statein the casing 610 to a ready state out of the casing. The rising, “popout,” or other external state change draws attention to the UI/actuator664 and signals the next step in the injection administering process.

In some embodiments of hand-held injection device, the button-typeUI/actuator may also be configured to rotate or spin as it undergoeschange from the dormant state to the ready state to further attract theattention of the patient or operator. In such embodiments, theUI/actuator may include an icon that spins as the UI/actuator spins, ormoreover, the UI/actuator may illuminate as it spins, the side wall ofthe UI/actuator may illuminate or be brightly colored, a sound may bemade by an audio speaker contained in the injection device as theUI/actuator spins, and any combination thereof. In other embodiment ofthe hand-held injection device, the button-type UI/actuator and theattention enhancements described above may also be concealed by aclosure which opens to allow the UI/actuator to rise or “pop out.”

In still further embodiments, the UI/actuator of the hand-held injectiondevice may also comprise a display that turns on if the body contactsensor of the injection device senses proper contact with the body ofthe patient to attract the attention of the patient or operator andsignal the next step of the injection process. In some embodiments, thedisplay may also be concealed by a closure that opens to reveal theUI/actuator display, as the body contact sensor of the injection devicesenses proper contact with the body of the patient. In such embodiments,further attention may brought to the UI/actuator-display by causing itto display flashing or brightly colored images as it turns on or isrevealed by the closure. In addition, a sound may be combined with theturning on or revealing of the UI/actuator in such embodiments, whichsound can be made by an audio speaker contained in the injection device.

The above description describes various systems and methods for use witha drug delivery device. It should be clear that the system, drugdelivery device or methods can further comprise use of a medicamentlisted below with the caveat that the following list should neither beconsidered to be all inclusive nor limiting. The medicament will becontained in a reservoir. In some instances, the reservoir is a primarycontainer that is either filled or pre-filled for treatment with themedicament. The primary container can be a cartridge or a pre-filledsyringe.

For example, the drug delivery device or more specifically the reservoirof the device may be filled with colony stimulating factors, such asgranulocyte colony-stimulating factor (G-CSF). Such G-CSF agentsinclude, but are not limited to, Neupogen® (filgrastim) and Neulasta®(pegfilgrastim). In various other embodiments, the drug delivery devicemay be used with various pharmaceutical products, such as anerythropoiesis stimulating agent (ESA), which may be in a liquid or alyophilized form. An ESA is any molecule that stimulates erythropoiesis,such as Epogen® (epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo®(epoetin delta), Mircera® (methyoxy polyethylene glycol-epoetin beta),Hematide®, MRK-2578, INS-22, Retacrit® (epoetin zeta), Neorecormon®(epoetin beta), Silapo® (epoetin zeta), Binocrit® (epoetin alfa),epoetin alfa Hexal, Abseamed® (epoetin alfa), Ratioepo® (epoetin theta),Eporatio® (epoetin theta), Biopoin® (epoetin theta), epoetin alfa,epoetin beta, epoetin zeta, epoetin theta, and epoetin delta, as well asthe molecules or variants or analogs thereof as disclosed in thefollowing patents or patent applications, each of which is hereinincorporated by reference in its entirety: U.S. Pat. Nos. 4,703,008;5,441,868; 5,547,933; 5,618,698; 5,621,080; 5,756,349; 5,767,078;5,773,569; 5,955,422; 5,986,047; 6,583,272; 7,084,245; and 7,271,689;and PCT Publication Nos. WO 91/05867; WO 95/05465; WO 96/40772; WO00/24893; WO 01/81405; and WO 2007/136752.

An ESA can be an erythropoiesis stimulating protein. As used herein,“erythropoiesis stimulating protein” means any protein that directly orindirectly causes activation of the erythropoietin receptor, forexample, by binding to and causing dimerization of the receptor.Erythropoiesis stimulating proteins include erythropoietin and variants,analogs, or derivatives thereof that bind to and activate erythropoietinreceptor; antibodies that bind to erythropoietin receptor and activatethe receptor; or peptides that bind to and activate erythropoietinreceptor. Erythropoiesis stimulating proteins include, but are notlimited to, epoetin alfa, epoetin beta, epoetin delta, epoetin omega,epoetin iota, epoetin zeta, and analogs thereof, pegylatederythropoietin, carbamylated erythropoietin, mimetic peptides (includingEMP1/hematide), and mimetic antibodies. Exemplary erythropoiesisstimulating proteins include erythropoietin, darbepoetin, erythropoietinagonist variants, and peptides or antibodies that bind and activateerythropoietin receptor (and include compounds reported in U.S.Publication Nos. 2003/0215444 and 2006/0040858, the disclosures of eachof which is incorporated herein by reference in its entirety) as well aserythropoietin molecules or variants or analogs thereof as disclosed inthe following patents or patent applications, which are each hereinincorporated by reference in its entirety: U.S. Pat. Nos. 4,703,008;5,441,868; 5,547,933; 5,618,698; 5,621,080; 5,756,349; 5,767,078;5,773,569; 5,955,422; 5,830,851; 5,856,298; 5,986,047; 6,030,086;6,310,078; 6,391,633; 6,583,272; 6,586,398; 6,900,292; 6,750,369;7,030,226; 7,084,245; and 7,217,689; U.S. Publication Nos. 2002/0155998;2003/0077753; 2003/0082749; 2003/0143202; 2004/0009902; 2004/0071694;2004/0091961; 2004/0143857; 2004/0157293; 2004/0175379; 2004/0175824;2004/0229318; 2004/0248815; 2004/0266690; 2005/0019914; 2005/0026834;2005/0096461; 2005/0107297; 2005/0107591; 2005/0124045; 2005/0124564;2005/0137329; 2005/0142642; 2005/0143292; 2005/0153879; 2005/0158822;2005/0158832; 2005/0170457; 2005/0181359; 2005/0181482; 2005/0192211;2005/0202538; 2005/0227289; 2005/0244409; 2006/0088906; and2006/0111279; and PCT Publication Nos. WO 91/05867; WO 95/05465; WO99/66054; WO 00/24893; WO 01/81405; WO 00/61637; WO 01/36489; WO02/014356; WO 02/19963; WO 02/20034; WO 02/49673; WO 02/085940; WO03/029291; WO 2003/055526; WO 2003/084477; WO 2003/094858; WO2004/002417; WO 2004/002424; WO 2004/009627; WO 2004/024761; WO2004/033651; WO 2004/035603; WO 2004/043382; WO 2004/101600; WO2004/101606; WO 2004/101611; WO 2004/106373; WO 2004/018667; WO2005/001025; WO 2005/001136; WO 2005/021579; WO 2005/025606; WO2005/032460; WO 2005/051327; WO 2005/063808; WO 2005/063809; WO2005/070451; WO 2005/081687; WO 2005/084711; WO 2005/103076; WO2005/100403; WO 2005/092369; WO 2006/50959; WO 2006/02646; and WO2006/29094.

Examples of other pharmaceutical products for use with the device mayinclude, but are not limited to, antibodies such as Vectibix®(panitumumab), Xgeva™ (denosumab) and Prolia™ (denosamab); otherbiological agents such as Enbrel® (etanercept, TNF-receptor/Fc fusionprotein, TNF blocker), Neulasta® (pegfilgrastim, pegylated filgastrim,pegylated G-CSF, pegylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF,hu-MetG-CSF), and Nplate® (romiplostim); small molecule drugs such asSensipar® (cinacalcet). The device may also be used with a therapeuticantibody, a polypeptide, a protein or other chemical, such as an iron,for example, ferumoxytol, iron dextrans, ferric glyconate, and ironsucrose. The pharmaceutical product may be in liquid form, orreconstituted from lyophilized form.

Among particular illustrative proteins are the specific proteins setforth below, including fusions, fragments, analogs, variants orderivatives thereof:

OPGL specific antibodies, peptibodies, and related proteins, and thelike (also referred to as RANKL specific antibodies, peptibodies and thelike), including fully humanized and human OPGL specific antibodies,particularly fully humanized monoclonal antibodies, including but notlimited to the antibodies described in PCT Publication No. WO 03/002713,which is incorporated herein in its entirety as to OPGL specificantibodies and antibody related proteins, particularly those having thesequences set forth therein, particularly, but not limited to, thosedenoted therein: 9H7; 18B2; 2D8; 2E11; 16E1; and 22B3, including theOPGL specific antibodies having either the light chain of SEQ ID NO:2 asset forth therein in FIG. 2 and/or the heavy chain of SEQ ID NO:4, asset forth therein in FIG. 4, each of which is individually andspecifically incorporated by reference herein in its entirety fully asdisclosed in the foregoing publication;

Myostatin binding proteins, peptibodies, and related proteins, and thelike, including myostatin specific peptibodies, particularly thosedescribed in U.S. Publication No. 2004/0181033 and PCT Publication No.WO 2004/058988, which are incorporated by reference herein in theirentirety particularly in parts pertinent to myostatin specificpeptibodies, including but not limited to peptibodies of the mTN8-19family, including those of SEQ ID NOS:305-351, including TN8-19-1through TN8-19-40, TN8-19 con1 and TN8-19 con2; peptibodies of the mL2family of SEQ ID NOS:357-383; the mL15 family of SEQ ID NOS:384-409; themL17 family of SEQ ID NOS:410-438; the mL20 family of SEQ IDNOS:439-446; the mL21 family of SEQ ID NOS:447-452; the mL24 family ofSEQ ID NOS:453-454; and those of SEQ ID NOS:615-631, each of which isindividually and specifically incorporated by reference herein in theirentirety fully as disclosed in the foregoing publication;

IL-4 receptor specific antibodies, peptibodies, and related proteins,and the like, particularly those that inhibit activities mediated bybinding of IL-4 and/or IL-13 to the receptor, including those describedin PCT Publication No. WO 2005/047331 or PCT Application No.PCT/US2004/37242 and in U.S. Publication No. 2005/112694, which areincorporated herein by reference in their entirety particularly in partspertinent to IL-4 receptor specific antibodies, particularly suchantibodies as are described therein, particularly, and withoutlimitation, those designated therein: L1H1; L1H2; L1H3; L1H4; L1H5;L1H6; L1H7; L1H8; L1H9; L1H10; L1H11; L2H1; L2H2; L2H3; L2H4; L2H5;L2H6; L2H7; L2H8; L2H9; L2H10; L2H11; L2H12; L2H13; L2H14; L3H1; L4H1;L5H1; L6H1, each of which is individually and specifically incorporatedby reference herein in its entirety fully as disclosed in the foregoingpublication;

Interleukin 1-receptor 1 (“IL1-R1”) specific antibodies, peptibodies,and related proteins, and the like, including but not limited to thosedescribed in U.S. Publication No. 2004/097712, which is incorporatedherein by reference in its entirety in parts pertinent to IL1-R1specific binding proteins, monoclonal antibodies in particular,especially, without limitation, those designated therein: 15CA, 26F5,27F2, 24E12, and 10H7, each of which is individually and specificallyincorporated by reference herein in its entirety fully as disclosed inthe aforementioned publication;

Ang2 specific antibodies, peptibodies, and related proteins, and thelike, including but not limited to those described in PCT PublicationNo. WO 03/057134 and U.S. Publication No. 2003/0229023, each of which isincorporated herein by reference in its entirety particularly in partspertinent to Ang2 specific antibodies and peptibodies and the like,especially those of sequences described therein and including but notlimited to: L1(N); L1(N) WT; L1(N) 1K WT; 2×L1(N); 2×L1(N) WT; Con4 (N),Con4 (N) 1K WT, 2×Con4 (N) 1K; L1C; L1C 1K; 2×L1C; Con4C; Con4C 1K;2×Con4C 1K; Con4-L1 (N); Con4-L1C; TN-12-9 (N); C17 (N); TN8-8(N);TN8-14 (N); Con 1 (N), also including anti-Ang 2 antibodies andformulations such as those described in PCT Publication No. WO2003/030833 which is incorporated herein by reference in its entirety asto the same, particularly Ab526; Ab528; Ab531; Ab533; Ab535; Ab536;Ab537; Ab540; Ab543; Ab544; Ab545; Ab546; A551; Ab553; Ab555; Ab558;Ab559; Ab565; AbF1AbFD; AbFE; AbFJ; AbFK; AbG1D4; AbGC1E8; AbH1C12;AblA1; AblF; AblK, AblP; and AblP, in their various permutations asdescribed therein, each of which is individually and specificallyincorporated by reference herein in its entirety fully as disclosed inthe foregoing publication;

NGF specific antibodies, peptibodies, and related proteins, and the likeincluding, in particular, but not limited to those described in U.S.Publication No. 2005/0074821 and U.S. Pat. No. 6,919,426, which areincorporated herein by reference in their entirety particularly as toNGF-specific antibodies and related proteins in this regard, includingin particular, but not limited to, the NGF-specific antibodies thereindesignated 4D4, 4G6, 6H9, 7H2, 14D10 and 14D11, each of which isindividually and specifically incorporated by reference herein in itsentirety fully as disclosed in the foregoing publication;

CD22 specific antibodies, peptibodies, and related proteins, and thelike, such as those described in U.S. Pat. No. 5,789,554, which isincorporated herein by reference in its entirety as to CD22 specificantibodies and related proteins, particularly human CD22 specificantibodies, such as but not limited to humanized and fully humanantibodies, including but not limited to humanized and fully humanmonoclonal antibodies, particularly including but not limited to humanCD22 specific IgG antibodies, such as, for instance, a dimer of ahuman-mouse monoclonal hLL2 gamma-chain disulfide linked to ahuman-mouse monoclonal hLL2 kappa-chain, including, but limited to, forexample, the human CD22 specific fully humanized antibody inEpratuzumab, CAS registry number 501423-23-0;

IGF-1 receptor specific antibodies, peptibodies, and related proteins,and the like, such as those described in PCT Publication No. WO06/069202, which is incorporated herein by reference in its entirety asto IGF-1 receptor specific antibodies and related proteins, includingbut not limited to the IGF-1 specific antibodies therein designatedL1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11,L12H12, L13H13, L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20H20,L21H21, L22H22, L23H23, L24H24, L25H25, L26H26, L27H27, L28H28, L29H29,L30H30, L31H31, L32H32, L33H33, L34H34, L35H35, L36H36, L37H37, L38H38,L39H39, L40H40, L41H41, L42H42, L43H43, L44H44, L45H45, L46H46, L47H47,L48H48, L49H49, L50H50, L51H51, L52H52, and IGF-1R-binding fragments andderivatives thereof, each of which is individually and specificallyincorporated by reference herein in its entirety fully as disclosed inthe foregoing publication;

Also among non-limiting examples of anti-IGF-1R antibodies for use inthe methods and compositions of the present invention are each and allof those described in:

-   -   (i) U.S. Publication No. 2006/0040358 (published Feb. 23, 2006),        2005/0008642 (published Jan. 13, 2005), 2004/0228859 (published        Nov. 18, 2004), including but not limited to, for instance,        antibody 1A (DSMZ Deposit No. DSM ACC 2586), antibody 8 (DSMZ        Deposit No. DSM ACC 2589), antibody 23 (DSMZ Deposit No. DSM        ACC 2588) and antibody 18 as described therein;    -   (ii) PCT Publication No. WO 06/138729 (published Dec. 28, 2006)        and WO 05/016970 (published Feb. 24, 2005), and Lu et al.        (2004), J. Biol. Chem. 279:2856-2865, including but not limited        to antibodies 2F8, A12, and IMC-A12 as described therein;    -   (iii) PCT Publication No. WO 07/012614 (published Feb. 1, 2007),        WO 07/000328 (published Jan. 4, 2007), WO 06/013472 (published        Feb. 9, 2006), WO 05/058967 (published Jun. 30, 2005), and WO        03/059951 (published Jul. 24, 2003);    -   (iv) U.S. Publication No. 2005/0084906 (published Apr. 21,        2005), including but not limited to antibody 7C10, chimaeric        antibody C7C10, antibody h7C10, antibody 7H2M, chimaeric        antibody *7C10, antibody GM 607, humanized antibody 7C10 version        1, humanized antibody 7C10 version 2, humanized antibody 7C10        version 3, and antibody 7H2HM, as described therein;    -   (v) U.S. Publication Nos. 2005/0249728 (published Nov. 10,        2005), 2005/0186203 (published Aug. 25, 2005), 2004/0265307        (published Dec. 30, 2004), and 2003/0235582 (published Dec.        25, 2003) and Maloney et al. (2003), Cancer Res. 63:5073-5083,        including but not limited to antibody EM164, resurfaced EM164,        humanized EM164, huEM164 v1.0, huEM164 v1.1, huEM164 v1.2, and        huEM164 v1.3 as described therein;    -   (vi) U.S. Pat. No. 7,037,498 (issued May 2, 2006), U.S.        Publication Nos. 2005/0244408 (published Nov. 30, 2005) and        2004/0086503 (published May 6, 2004), and Cohen, et al. (2005),        Clinical Cancer Res. 11:2063-2073, e.g., antibody CP-751,871,        including but not limited to each of the antibodies produced by        the hybridomas having the ATCC accession numbers PTA-2792,        PTA-2788, PTA-2790, PTA-2791, PTA-2789, PTA-2793, and antibodies        2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2, and 4.17.3, as described        therein;    -   (vii) U.S. Publication Nos. 2005/0136063 (published Jun.        23, 2005) and 2004/0018191 (published Jan. 29, 2004), including        but not limited to antibody 19D12 and an antibody comprising a        heavy chain encoded by a polynucleotide in plasmid 15H12/19D12        HCA (?4), deposited at the ATCC under number PTA-5214, and a        light chain encoded by a polynucleotide in plasmid 15H12/19D12        LCF (?), deposited at the ATCC under number PTA-5220, as        described therein; and    -   (viii) U.S. Publication No. 2004/0202655 (published Oct. 14,        2004), including but not limited to antibodies PINT-6A1,        PINT-7A2, PINT-7A4, PINT-7A5, PINT-7A6, PINT-8A1, PINT-9A2,        PINT-11A1, PINT-11A2, PINT-11A3, PINT-11A4, PINT-11A5,        PINT-11A7, PINT-11A12, PINT-12A1, PINT-12A2, PINT-12A3,        PINT-12A4, and PINT-12A5, as described therein; each and all of        which are herein incorporated by reference in their entireties,        particularly as to the aforementioned antibodies, peptibodies,        and related proteins and the like that target IGF-1 receptors;

B-7 related protein 1 specific antibodies, peptibodies, related proteinsand the like (“B7RP-1,” also is referred to in the literature as B7H2,ICOSL, B7h, and CD275), particularly B7RP-specific fully humanmonoclonal IgG2 antibodies, particularly fully human IgG2 monoclonalantibody that binds an epitope in the first immunoglobulin-like domainof B7RP-1, especially those that inhibit the interaction of B7RP-1 withits natural receptor, ICOS, on activated T cells in particular,especially, in all of the foregoing regards, those disclosed in U.S.Publication No. 2008/0166352 and PCT Publication No. WO 07/011941, whichare incorporated herein by reference in their entireties as to suchantibodies and related proteins, including but not limited to antibodiesdesignated therein as follow: 16H (having light chain variable and heavychain variable sequences SEQ ID NO:1 and SEQ ID NO:7 respectivelytherein); 5D (having light chain variable and heavy chain variablesequences SEQ ID NO:2 and SEQ ID NO:9 respectively therein); 2H (havinglight chain variable and heavy chain variable sequences SEQ ID NO:3 andSEQ ID NO:10 respectively therein); 43H (having light chain variable andheavy chain variable sequences SEQ ID NO:6 and SEQ ID NO:14 respectivelytherein); 41H (having light chain variable and heavy chain variablesequences SEQ ID NO:5 and SEQ ID NO:13 respectively therein); and 15H(having light chain variable and heavy chain variable sequences SEQ IDNO:4 and SEQ ID NO:12 respectively therein), each of which isindividually and specifically incorporated by reference herein in itsentirety fully as disclosed in the foregoing publication;

IL-15 specific antibodies, peptibodies, and related proteins, and thelike, such as, in particular, humanized monoclonal antibodies,particularly antibodies such as those disclosed in U.S. Publication Nos.2003/0138421; 2003/023586; and 2004/0071702; and U.S. Pat. No.7,153,507, each of which is incorporated herein by reference in itsentirety as to IL-15 specific antibodies and related proteins, includingpeptibodies, including particularly, for instance, but not limited to,HuMax IL-15 antibodies and related proteins, such as, for instance,146B7;

IFN gamma specific antibodies, peptibodies, and related proteins and thelike, especially human IFN gamma specific antibodies, particularly fullyhuman anti-IFN gamma antibodies, such as, for instance, those describedin U.S. Publication No. 2005/0004353, which is incorporated herein byreference in its entirety as to IFN gamma specific antibodies,particularly, for example, the antibodies therein designated 1118;1118*; 1119; 1121; and 1121*. The entire sequences of the heavy andlight chains of each of these antibodies, as well as the sequences oftheir heavy and light chain variable regions and complementaritydetermining regions, are each individually and specifically incorporatedby reference herein in its entirety fully as disclosed in the foregoingpublication and in Thakur et al. (1999), Mol. Immunol. 36:1107-1115. Inaddition, description of the properties of these antibodies provided inthe foregoing publication is also incorporated by reference herein inits entirety. Specific antibodies include those having the heavy chainof SEQ ID NO:17 and the light chain of SEQ ID NO:18; those having theheavy chain variable region of SEQ ID NO:6 and the light chain variableregion of SEQ ID NO:8; those having the heavy chain of SEQ ID NO:19 andthe light chain of SEQ ID NO:20; those having the heavy chain variableregion of SEQ ID NO:10 and the light chain variable region of SEQ IDNO:12; those having the heavy chain of SEQ ID NO:32 and the light chainof SEQ ID NO:20; those having the heavy chain variable region of SEQ IDNO:30 and the light chain variable region of SEQ ID NO:12; those havingthe heavy chain sequence of SEQ ID NO:21 and the light chain sequence ofSEQ ID NO:22; those having the heavy chain variable region of SEQ IDNO:14 and the light chain variable region of SEQ ID NO:16; those havingthe heavy chain of SEQ ID NO:21 and the light chain of SEQ ID NO:33; andthose having the heavy chain variable region of SEQ ID NO:14 and thelight chain variable region of SEQ ID NO:31, as disclosed in theforegoing publication. A specific antibody contemplated is antibody 1119as disclosed in the foregoing U.S. publication and having a completeheavy chain of SEQ ID NO:17 as disclosed therein and having a completelight chain of SEQ ID NO:18 as disclosed therein;

TALL-1 specific antibodies, peptibodies, and the related proteins, andthe like, and other TALL specific binding proteins, such as thosedescribed in U.S. Publication Nos. 2003/0195156 and 2006/0135431, eachof which is incorporated herein by reference in its entirety as toTALL-1 binding proteins, particularly the molecules of Tables 4 and 5B,each of which is individually and specifically incorporated by referenceherein in its entirety fully as disclosed in the foregoing publications;

Parathyroid hormone (“PTH”) specific antibodies, peptibodies, andrelated proteins, and the like, such as those described in U.S. Pat. No.6,756,480, which is incorporated herein by reference in its entirety,particularly in parts pertinent to proteins that bind PTH;

Thrombopoietin receptor (“TPO-R”) specific antibodies, peptibodies, andrelated proteins, and the like, such as those described in U.S. Pat. No.6,835,809, which is herein incorporated by reference in its entirety,particularly in parts pertinent to proteins that bind TPO-R;

Hepatocyte growth factor (“HGF”) specific antibodies, peptibodies, andrelated proteins, and the like, including those that target theHGF/SF:cMet axis (HGF/SF:c-Met), such as the fully human monoclonalantibodies that neutralize hepatocyte growth factor/scatter (HGF/SF)described in U.S. Publication No. 2005/0118643 and PCT Publication No.WO 2005/017107, huL2G7 described in U.S. Pat. No. 7,220,410 and OA-5d5described in U.S. Pat. Nos. 5,686,292 and 6,468,529 and in PCTPublication No. WO 96/38557, each of which is incorporated herein byreference in its entirety, particularly in parts pertinent to proteinsthat bind HGF;

TRAIL-R2 specific antibodies, peptibodies, related proteins and thelike, such as those described in U.S. Pat. No. 7,521,048, which isherein incorporated by reference in its entirety, particularly in partspertinent to proteins that bind TRAIL-R2;

Activin A specific antibodies, peptibodies, related proteins, and thelike, including but not limited to those described in U.S. PublicationNo. 2009/0234106, which is herein incorporated by reference in itsentirety, particularly in parts pertinent to proteins that bind ActivinA;

TGF-beta specific antibodies, peptibodies, related proteins, and thelike, including but not limited to those described in U.S. Pat. No.6,803,453 and U.S. Publication No. 2007/0110747, each of which is hereinincorporated by reference in its entirety, particularly in partspertinent to proteins that bind TGF-beta;

Amyloid-beta protein specific antibodies, peptibodies, related proteins,and the like, including but not limited to those described in PCTPublication No. WO 2006/081171, which is herein incorporated byreference in its entirety, particularly in parts pertinent to proteinsthat bind amyloid-beta proteins. One antibody contemplated is anantibody having a heavy chain variable region comprising SEQ ID NO:8 anda light chain variable region having SEQ ID NO:6 as disclosed in theforegoing publication;

c-Kit specific antibodies, peptibodies, related proteins, and the like,including but not limited to those described in U.S. Publication No.2007/0253951, which is incorporated herein by reference in its entirety,particularly in parts pertinent to proteins that bind c-Kit and/or otherstem cell factor receptors;

OX40L specific antibodies, peptibodies, related proteins, and the like,including but not limited to those described in U.S. Publication No.2006/0002929, which is incorporated herein by reference in its entirety,particularly in parts pertinent to proteins that bind OX40L and/or otherligands of the OX40 receptor; and

Other exemplary proteins, including Activase® (alteplase, tPA); Aranesp®(darbepoetin alfa); Epogen® (epoetin alfa, or erythropoietin); GLP-1,Avonex® (interferon beta-1a); Bexxar® (tositumomab, anti-CD22 monoclonalantibody); Betaseron® (interferon-beta); Campath® (alemtuzumab,anti-CD52 monoclonal antibody); Dynepo® (epoetin delta); Velcade®(bortezomib); MLN0002 (anti-?4137 mAb); MLN1202 (anti-CCR2 chemokinereceptor mAb); Enbrel® (etanercept, TNF-receptor/Fc fusion protein, TNFblocker); Eprex® (epoetin alfa); Erbitux® (cetuximab,anti-EGFR/HER1/c-ErbB-1); Genotropin® (somatropin, Human GrowthHormone); Herceptin® (trastuzumab, anti-HER2/neu (erbB2) receptor mAb);Humatrope® (somatropin, Human Growth Hormone); Humira® (adalimumab);insulin in solution; Infergen® (interferon alfacon-1); Natrecor®(nesiritide; recombinant human B-type natriuretic peptide (hBNP);Kineret® (anakinra); Leukine® (sargamostim, rhuGM-CSF); LymphoCide®(epratuzumab, anti-CD22 mAb); Benlysta™ (lymphostat B, belimumab,anti-BlyS mAb); Metalyse® (tenecteplase, t-PA analog); Mircera® (methoxypolyethylene glycol-epoetin beta); Mylotarg® (gemtuzumab ozogamicin);Raptiva® (efalizumab); Cimzia® (certolizumab pegol, CDP 870); Soliris™(eculizumab); pexelizumab (anti-05 complement); Numax® (MEDI-524);Lucentis® (ranibizumab); Panorex® (17-1A, edrecolomab); Trabio®(lerdelimumab); TheraCim hR3 (nimotuzumab); Omnitarg (pertuzumab, 2C4);Osidem® (IDM-1); OvaRex® (B43.13); Nuvion® (visilizumab); cantuzumabmertansine (huC242-DM1); NeoRecormon® (epoetin beta); Neumega®(oprelvekin, human interleukin-11); Neulasta® (pegylated filgastrim,pegylated G-CSF, pegylated hu-Met-G-CSF); Neupogen® (filgrastim, G-CSF,hu-MetG-CSF); Orthoclone OKT3® (muromonab-CD3, anti-CD3 monoclonalantibody); Procrit® (epoetin alfa); Remicade® (infliximab, anti-TNF?monoclonal antibody); Reopro® (abciximab, anti-GP IIb/IIia receptormonoclonal antibody); Actemra® (anti-IL6 Receptor mAb); Avastin®(bevacizumab), HuMax-CD4 (zanolimumab); Rituxan® (rituximab, anti-CD20mAb); Tarceva® (erlotinib); Roferon-A®-(interferon alfa-2a); Simulect®(basiliximab); Prexige® (lumiracoxib); Synagis® (palivizumab); 146B7-CHO(anti-IL15 antibody, see U.S. Pat. No. 7,153,507); Tysabri®(natalizumab, anti-?4integrin mAb); Valortim® (MDX-1303, anti-B.anthracis protective antigen mAb); ABthrax™; Vectibix® (panitumumab);Xolair® (omalizumab); ETI211 (anti-MRSA mAb); IL-1 trap (the Fc portionof human IgG1 and the extracellular domains of both IL-1 receptorcomponents (the Type I receptor and receptor accessory protein)); VEGFtrap (Ig domains of VEGFR1 fused to IgG1 Fc); Zenapax® (daclizumab);Zenapax® (daclizumab, anti-IL-2R? mAb); Zevalin® (ibritumomab tiuxetan);Zetia® (ezetimibe); Orencia® (atacicept, TACI-Ig); anti-CD80 monoclonalantibody (galiximab); anti-CD23 mAb (lumiliximab); BR2-Fc (huBR3/huFcfusion protein, soluble BAFF antagonist); CNTO 148 (golimumab, anti-TNF?mAb); HGS-ETR1 (mapatumumab; human anti-TRAIL Receptor-1 mAb);HuMax-CD20 (ocrelizumab, anti-CD20 human mAb); HuMax-EGFR (zalutumumab);M200 (volociximab, anti-?5?1 integrin mAb); MDX-010 (ipilimumab,anti-CTLA-4 mAb and VEGFR-1 (IMC-18F1); anti-BR3 mAb; anti-C. difficileToxin A and Toxin B C mAbs MDX-066 (CDA-1) and MDX-1388); anti-CD22dsFv-PE38 conjugates (CAT-3888 and CAT-8015); anti-CD25 mAb (HuMax-TAC);anti-CD3 mAb (NI-0401); adecatumumab; anti-CD30 mAb (MDX-060); MDX-1333(anti-IFNAR); anti-CD38 mAb (HuMax CD38); anti-CD40L mAb; anti-CriptomAb; anti-CTGF Idiopathic Pulmonary Fibrosis Phase I Fibrogen (FG-3019);anti-CTLA4 mAb; anti-eotaxin1 mAb (CAT-213); anti-FGF8 mAb;anti-ganglioside GD2 mAb; anti-ganglioside GM2 mAb; anti-GDF-8 human mAb(MYO-029); anti-GM-CSF Receptor mAb (CAM-3001); anti-HepC mAb (HuMaxHepC); anti-IFN? mAb (MEDI-545, MDX-1103); anti-IGF1R mAb; anti-IGF-1RmAb (HuMax-Inflam); anti-IL12 mAb (ABT-874); anti-IL12/IL23 mAb (CNTO1275); anti-IL13 mAb (CAT-354); anti-IL2Ra mAb (HuMax-TAC); anti-IL5Receptor mAb; anti-integrin receptors mAb (MDX-018, CNTO 95); anti-IP10Ulcerative Colitis mAb (MDX-1100); anti-LLY antibody; BMS-66513;anti-Mannose Receptor/hCG? mAb (MDX-1307); anti-mesothelin dsFv-PE38conjugate (CAT-5001); anti-PD1mAb (MDX-1106 (ONO-4538)); anti-PDGFR?antibody (IMC-3G3); anti-TGFß mAb (GC-1008); anti-TRAIL Receptor-2 humanmAb (HGS-ETR2); anti-TWEAK mAb; anti-VEGFR/Flt-1 mAb; anti-ZP3 mAb(HuMax-ZP3); NVS Antibody #1; and NVS Antibody #2.

Also included can be a sclerostin antibody, such as but not limited toromosozumab, blosozumab, or BPS 804 (Novartis). Further included can betherapeutics such as rilotumumab, bixalomer, trebananib, ganitumab,conatumumab, motesanib diphosphate, brodalumab, vidupiprant,panitumumab, denosumab, NPLATE, PROLIA, VECTIBIX or XGEVA. Additionally,included in the device can be a monoclonal antibody (IgG) that bindshuman Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), e.g. U.S.Pat. No. 8,030,547, U.S. Publication No. 2013/0064825, WO2008/057457,WO2008/057458, WO2008/057459, WO2008/063382, WO2008/133647,WO2009/100297, WO2009/100318, WO2011/037791, WO2011/053759,WO2011/053783, WO2008/125623, WO2011/072263, WO2009/055783,WO2012/0544438, WO2010/029513, WO2011/111007, WO2010/077854,WO2012/088313, WO2012/101251, WO2012/101252, WO2012/101253,WO2012/109530, and WO2001/031007.

Also included can be talimogene laherparepvec or another oncolytic HSVfor the treatment of melanoma or other cancers. Examples of oncolyticHSV include, but are not limited to talimogene laherparepvec (U.S. Pat.Nos. 7,223,593 and 7,537,924); OncoVEXGALV/CD (U.S. Pat. No. 7,981,669);OrienX010 (Lei et al. (2013), World J. Gastroenterol., 19:5138-5143);G207, 1716; NV1020; NV12023; NV1034 and NV1042 (Vargehes et al. (2002),Cancer Gene Ther., 9(12):967-978).

Also included are TIMPs. TIMPs are endogenous tissue inhibitors ofmetalloproteinases (TIMPs) and are important in many natural processes.TIMP-3 is expressed by various cells or and is present in theextracellular matrix; it inhibits all the major cartilage-degradingmetalloproteases, and may play a role in role in many degradativediseases of connective tissue, including rheumatoid arthritis andosteoarthritis, as well as in cancer and cardiovascular conditions. Theamino acid sequence of TIMP-3, and the nucleic acid sequence of a DNAthat encodes TIMP-3, are disclosed in U.S. Pat. No. 6,562,596, issuedMay 13, 2003, the disclosure of which is incorporated by referenceherein. Description of TIMP mutations can be found in U.S. PublicationNo. 2014/0274874 and PCT Publication No. WO 2014/152012.

Also included are antagonistic antibodies for human calcitoningene-related peptide (CGRP) receptor and bispecific antibody moleculethat target the CGRP receptor and other headache targets. Furtherinformation concerning these molecules can be found in PCT ApplicationNo. WO 2010/075238.

Additionally, a bispecific T cell engager antibody (BiTe), e.g.Blinotumomab can be used in the device. Alternatively, included can bean APJ large molecule agonist e.g., apelin or analogues thereof in thedevice. Information relating to such molecules can be found in PCTPublication No. WO 2014/099984.

In certain embodiments, the medicament comprises a therapeuticallyeffective amount of an anti-thymic stromal lymphopoietin (TSLP) or TSLPreceptor antibody. Examples of anti-TSLP antibodies that may be used insuch embodiments include, but are not limited to, those described inU.S. Pat. Nos. 7,982,016, and 8,232,372, and U.S. Publication No.2009/0186022. Examples of anti-TSLP receptor antibodies include, but arenot limited to, those described in U.S. Pat. No. 8,101,182. Inparticularly preferred embodiments, the medicament comprises atherapeutically effective amount of the anti-TSLP antibody designated asA5 within U.S. Pat. No. 7,982,016.

Although the drug delivery device, systems, and methods have beendescribed in terms of illustrative embodiments, it is not limitedthereto. Rather, the appended claims should be construed broadly toinclude other variants and embodiments of same, which may be made bythose skilled in the art without departing from the scope and range ofequivalents of the device, system, and method.

What is claimed is:
 1. A drug delivery device comprising: a casinghaving a bottom surface; a container for storing a drug received withinthe casing; a stopper movably disposed within the container forexpelling the drug; an injection drive comprising an energy sourceoperably coupled to the stopper for selectively moving the stopperthrough the container to expel the drug; a sensor having a first statewhen the drug delivery device is out of contact with a body of apatient, and having a second state when the drug delivery device is incontact with the body of the patient; a device activation mechanismoperably coupled to the sensor and the injection drive for selectivelyactivating the injection drive, wherein the drug delivery deviceundergoes an external state change from a dormant state, when the sensoroccupies the first state, to a ready state, upon the sensor occupyingthe second state; and an adhesive pad covering the bottom surface of thecasing, the adhesive pad adapted to removably attach the casing to apatient.
 2. The drug delivery device of claim 1, wherein the casingcomprises a top wall, a bottom wall, and side walls extending betweenthe top wall and the bottom wall; and the adhesive pad covers the entirebottom wall.
 3. The drug delivery device of claim 2, further comprisinga drug delivery member fluidly coupled to the container; and wherein thebottom wall of the casing and the adhesive pad include aligned first andsecond openings, the first openings adapted to receive the drug deliverymember therethrough and the second openings aligned with the sensor. 4.The drug delivery device of claim 1, further comprising a removablebarrier film disposed on the adhesive pad.
 5. The drug delivery deviceof claim 1, further comprising a light source, and wherein the externalstate change comprises the light source illuminating a surface.
 6. Thedrug delivery device of claim 1, further comprising a speaker; andwherein the external state change comprises sound played through thespeaker.
 7. The drug delivery device of claim 1, wherein the sensorcomprises an electrical sensor.
 8. The drug delivery device of claim 1,wherein the casing further comprises a closure or removable portionallowing insertion and removal of the container.
 9. The drug deliverydevice of claim 1, further comprising a processing unit, and wherein thesensor is adapted to send a signal to the processing unit in response tochanging from the first state to the second state.
 10. The drug deliverydevice of claim 9, wherein the sensor is adapted to send a second signalto the processing unit in response to changing from the second state tothe first state; and the processing unit is configured to controloperation of a deactivation sequence of the injection drive in responseto receiving the second signal.
 11. The drug delivery device of claim 9,wherein the processing unit is configured to receive an administrationrate for operation of the injection drive.
 12. A method of preparing adrug delivery device, the method comprising: providing a drug deliverydevice comprising: a casing having a bottom surface; a container forstoring a drug; a stopper movably disposed within the container forexpelling the drug, a drug delivery member fluidly coupled to thecontainer; an injection drive including an energy source operablycoupled to the stopper for selectively moving the stopper through thecontainer to expel the drug, a sensor; a device activation mechanismoperably coupled to the sensor and the injection drive; a processingunit operably coupled to the sensor and the device activation mechanism;and an adhesive pad covering the bottom surface of the casing andadapted to removably attach the casing to a patient, the adhesive padhaving a first opening adapted to receive the drug delivery membertherethrough and a second opening aligned with the sensor; adhering thedrug delivery device around an injection site with the adhesive pad;detecting contact between the drug delivery device and the injectionsite with the sensor, causing the sensor to change from a first state toa second state; when the sensor occupies the second state, deliveringcontact information to the processing unit with the sensor, the contactinformation indicative of the relationship between the drug deliverydevice and the injection site; upon receiving the contact information,causing the drug delivery device to undergo an external state changefrom a dormant state to a ready state, for drawing attention to thedevice activation mechanism and signaling that the drug delivery deviceis ready for use.
 13. The method according to claim 12, wherein causingthe drug delivery device to undergo the external state change comprisesactivating a light source to illuminate a surface and activating aspeaker to emit sound.
 14. The method according to claim 12, whereindelivering contact information to the processing unit comprisesdelivering an electrical signal to the processing unit from the sensor.15. The method according to claim 12, further comprising receiving thecontainer in an interior of the casing through a closure or removableportion thereof.